We have been studying tumor cell motility as a requirement for the metastatic dissemination of malignant cells. The autocrine motility factor (AMF) from human melanoma cells has been purified to homogeneity and its N-terminal sequence determined. The material is highly potent (50 pmol), a labile protein, and has an Mr about 60-65 kDa. A protein that is a candidate for a motility receptor on these cells has been identified by a monoclonal antibody. The latter inhibits migration of cells to a variety of stimuli. Type IV collagen, a chemoattractant for the melanoma cells, stimulates a rapid transient mobilization of intracellular calcium; this suggests a role for such Ca++ pools in the induction of the motile response by type IV collagen. Type I collagen does not stimulate motility. Insulin-like growth factor-I (IGF-I) previously shown to stimulate motility via a type I receptor, has now been demonstrated to stimulate a receptor-associated tyrosine kinase. This study provides insight into the signal transduction mechanism for IGF-I, an agent that may direct homing of metastatic cells. Preliminary results suggest that granulocyte-macrophage colony stimulating factor may also induce tumor cell migration. In collaborative studies with other investigators, it has been shown that rat prostatic carcinoma cells produce an AMF different from that of melanoma cells, and that IGF-II stimulates motility in rhabdomyosarcoma cells via a receptor distinct from the type I. These results emphasize the heterogeneity and versatility of malignant tumor cells during their metastatic dissemination.